线粒体融合、分裂与神经变性疾病

线粒体是一种处于高度运动状态的频繁地进行融合与分裂的细胞器.在生理状态下,线粒体的融合与分裂处于一种平衡的状态，这种平衡受线粒体融合蛋白1/2（Mfn1/2）、视神经萎缩蛋白1（OPA1）和动力相关蛋白1（Drp1）的调节. Mfn1/2介导线粒体外膜的融合，而OPA1则参与线粒体内膜的融合，这些蛋白受泛素化和蛋白水解的调控. Drp1参与线粒体的分裂过程，受多种翻译后修饰的调节，如磷酸化、泛素化、SUMO化和S 硝基化.对于神经元来说,线粒体融合分裂的动态平衡对保证神经元末梢长距离运输和能量平均分布是非常重要的.因此,线粒体融合分裂异常可能是许多神经变性疾病的致病因素之一.对线粒体融合而言,Mfn2错义突变将导致遗传性运动感觉神经病2型（CMT2A）；OPA1错义突变将引起显性遗传性视神经萎缩(ADOA)，而就线粒体分裂而言，Drp1突变与多系统功能障碍的新生儿致死性相关.

Deregulation of Mitochondrial Fusion and Fission in Neurodegenerative Diseases

Mitochondria are dynamic organelles that continually undergo fusion and fission. At steady state, there is a balance between mitochondrial fusion and fission, the balance is regulated by mitofusin1/2（Mfn1/2）, optic atrophy 1（OPA1）and dynamin related protein1（Drp1）. Mfn1/2 mediate outer membrane fusion, and OPA1subsequently mediates inner membrane fusion. These proteins are regulated by proteolysis and ubiquitination. Drp1 involves in mitochondrial fission, several different post translational modifications, including phosphorylation, ubiquitination,sumoylation, and s nitrosylation of Drp1 regulate its interaction with mitochondria. In neurons, the dynamic of mitochondrial fusion and fission are important for the nerve endings of long distance transportation and the average energy distribution, so the unbalance of mitochondrial fusion and fission is one of the most frequent causes for neurodegenerative diseases. In terms of fusion, heterozygous mutations in Mfn2 and OPA1 cause autosomal dominant axonal Charcot Marie Tooth type 2A (CMT2A) and autosomal dominant optic atrophy (ADOA), respectively. In terms of fission, a mutation in Drp1 has been linked to neonatal lethality with multisystem failure.